The present invention relates to novel drugs for prevention and treatment of myocarditis, dilated cardiomyopathy and heart failure.
Myocarditis is sometimes the result of infection by a virus or bacterium or a stimulus response to drugs or the like, and sometimes an autoimmunity, and it includes a group of diseases provoked by cardiomyopathy due to inflammation of cardiac muscle. A kind of myocarditis is chronic due to repeated aggravation and amelioration of the inflammation or continuous inflammation, eventually progressing to dilated cardiomyopathy.
The typical pathology of dilated cardiomyopathy includes dilation of the ventricle and contraction deficiency, and heart failure symptoms appear in 75-95% of patients, often with complications of arrhythmic death (sudden death) or thrombosis and embolism during the course of the disease. It is an intractable disease with a mortality rate of approximately fifty percent within 5 years of onset, and it accounts for half of the heart transplant patients in Europe and the U.S. It is therefore important to promptly achieve amelioration of acute myocarditis from the acute stage to prevent it from becoming chronic or intractable (Junkanki NOW, Vol.6, xe2x80x9cCardiomyopathy and Myocarditisxe2x80x9d, Nankodo Publishing).
No successful therapy has yet been established for this disease, and no effective therapeutic agent has been provided. It is ardently desired, therefore, to develop a drug that can suppress the necrosis of cardiac muscle cells and infiltration of inflammatory cells in myocarditis, in order to inhibit increase in heart weight and lead to improved survival rates.
Although the cause of myocarditis has not been thoroughly elucidated, reports of viral genes in cardiac muscle biopsy tissue from acute stage myocarditis and dilated cardiomyopathy patients suggest a viral infection link in almost all cases (Junkanki NOW, Vol.6, xe2x80x9cCardiomyopathy and Myocarditisxe2x80x9d, Nankodo Publishing).
Nitric oxide (NO) is biosynthesized from L-arginine as the substrate by NO synthase (NOs). Currently three isozymes of NOS have been found (Moncada, S. and Higgs, A. (1993) N. Eng. J. Med. 329: 2002-2012). Expression of inducible NOS (iNOs) is induced in various types of tissues and cells by endotoxins and cytokines (Forstermann U, et al. (1995) Biochem. Pharmacol. 50, 1321-1332).
Marked increase in NO production has been reported in myocarditis, dilated cardiomyopathy and heart failure patients (De Belder A J, et al. (1993) Lancet 341, 84-85; Habib F M, et al. (1996) Lancet 347, 1151-1155; Haywood G A, et al. (1994) Circulation 93, 1087-1094). Also, arginine derivatives and aminoguanidine, which are known as iNOS enzyme inhibitors, have been reported to exhibit a pharmacological effect in diseased animal models (Moncada S and Higgs E A (1995) PASEB J. 9, 1319-1330).
Thus, excess NO produced as a result of induced iNOS expression is implicated as a cause of myocarditis, dilated cardiomyopathy and heart failure.
In addition, tumor mecrosis factor (TNF)-xcex1, a cytokine produced from several kinds of cells including rmacrophages, is believed to be an important mediator of inflammation (Vassalli, P. (1992) Annu. Rev. Immunol. 10: 411-452). There is growing evidence that the excessive production of TNF-xcex1 damages normal cells and causes various pathosis (Muto, Y., et. al. (1988) Lancet 2: 72-74, Sharief, M. K. and Hentges, R. (1991) N. Engl. J. Med. 325: 467-472). Increase of TNF-xcex1 levels in the blood, like NO, has also been found in myocarditis, dilated cardiomyopathy and heart failure patients (Matsumori A, et al. (1994) Br. Heart J. 72, 561-566, Levine B, et al. (1990) N. Engl. J. Med. 323, 236-241). Antibodies for TNF-xcex1 have been demonstrated to be effective in animal models of myocarditis (Yamada T, et al. (1994) Circulation 89, 846-851).
Such findings have shown that excess production of TNF-xcex1 leads to and exacerbates myocarditis, dilated cardiomyopathy and heart failure, and it is therefore necessary to inhibit production of TNF-xcex1 as well as NO.
Interleukin (IL)-1xcex2 also increases markedly in the blood of acute myocarditis patients, and a good correlation has been found between IL-1xcex2 expression in chronic stage cardiac muscle and the heart/body weight ratio and extent of cardiac tissue fibrosis, in animal models of myocarditis (Shioi T, et al. (1996) Circulation 94, 2930-2937), while it has also been reported that administration of IL-1xcex2 to animals provokes cardiomyopathy or myocarditis (Lane J R, et al. (1992) J. Exp. Med. 175, 1123-1129; Japanese Unexamined Patent Publication No. 10-273445), thus also implicating IL-1xcex2 as one of these pathogenesis.
No therapeutic agents for cardiomyopathy or myocarditis have been reported that improve survival rates, but antibody that inhibits binding of the selectin an adhesion molecule, is being studied (Japanese Unexamined Patent Publication No. 10-273445).
Thus, iNOS, inflammatory cytokines such as TNF-xcex1, IL-1xcex2, etc. and adhesion molecules have all been implicated in myocarditis, dilated cardiomyopathy and heart failure (Habib F M, et al. (1996) Lancet 347, 1151-1155). However, numerous other causatory inflammatory mediators have been found (Matsumori A (1997) Jpn. Circ. J. 61, 275-291), and the fact that these pathological factors cannot be specified to a single mediator has complicated efforts to develop effective treatment agents. Given this current situation, there are doubts against the effectiveness of treatment or prevention using, for example, antibodies that recognize one antigen or substances that inhibit binding of adhesion molecules such as selecting. Therefore, there is a desire for low molecular compounds that, instead of suppressing only expression of specific inflammatory mediators, can broadly inhibit production and expression of proteins implicated as causes of inflammation.
NF-xcexaB is a protein that regulates gene expression and is one of the so-called transcription factors. When normal cells are stimulated with an inflammatory cytokine such as IL-1xcex2 and TNF-xcex1, a lipopolysaccharide, or ultraviolet rays, NF-xcexaB translocates from the cytoplasm into the nucleus where they bind to specific nucleotide sequences on the genomic DNA and thereby become involved in the expression of various genes (Blackwell, T. S. and Christman, J. W. (1997) Am. J. Respir. Cell Mol. Biol. 17: 3-9).
Although the genes coding for iNOS, inflammatory cytokines such TNF-xcex1 and IL-1xcex2 and adhesion molecules such as P selectin are completely distinct genes, in the expression regulatory regions of these genomic genes, there are consensus regions to which NF-xcexaB binds, and activation of NF-xcexaB has been shown to be important for expression of all of these proteins (Ghosh S, et al. (1998) Annu. Rev. Immunol. 16, 225-260).
Many genes that are involved in immunological inflammatory reactions under expression control by NF-xcexaB are recognized, including inflammatory cytokines such as IL-6 and IL-8, as well as cell adhesion molecules such as ICAM-1, VCAM-1 and ELAM-1 or the like (Collins, T., et al. (1995) Faseb. J. 9: 899-909). Furthermore, it is known that inflammatory cytokines, when bound to receptors, transduce NF-xcexaB-activating signals via various routes, and this fact is believed to be cause that further aggravates inflammation. Thus, the activation of NF-xcexaB in inflammation is understood as an pathogenesis and aggravating factor of diseases (Baeuerle, P. A. and Baichwal., V. R. (1997) Adv. Immunol. 65: 111-137).
NF-xcexaB inhibitors are characterized by inhibiting expression of iNOS, TNF-xcex1 and IL-1xcex2 at the genetic level in cells and tissues, thereby suppressing production of two or more among the inflammation mediators such as NO, TNF-xcex1 and IL-1xcex2 at once with a single agent, and they are expected to exhibit therapeutic effects against various diseases (Lee J C (1994) Ann. Report Med. Chem. 29, 235-244).
For example, the compound BAY11-7083, which has an inhibitory effect on NF-xcexaB, is reported to exhibit an effect in rat adjuvant arthritis (Pierce J W, et al. (1997) J. Biol. Chem. 272, 21096-21103). However, very few studies have examined the effect of administering NF-xcexaB inhibitors to animal models of specific diseases.
Several compounds are currently known as NF-xcexaB inhibitors, such as substituted pyrimidine derivatives (WO9709315, WO9709325, J. Med. Chem., 41, 413 (1998)), xanthine derivatives (Japanese Unexamined Patent Publication No. 9-227561) and isoquinoline derivatives (Japanese Unexamined Patent Publication No. 10-87491). As compounds with excellent NF-xcexaB inhibiting effects there may be mentioned phenylmethylbenzoquinone derivatives (WO9948491) and indan derivatives (WO0005234).
However, nothing is known about the therapeutic or preventive effects of these derivatives on myocarditis, dilated cardiomyopathy and heart failure. Moreover, no reports may be found regarding the therapeutic or preventive effects of using NF-xcexaB inhibitors for myocarditis, dilated cardiomyopathy and heart failure. Also completely unknown are the effects of these inhibitors in terms of suppressing expression of the proteins implicated as possible pathogenesis, even for any one of the target proteins.
Thus, while excess production of numerous inflammatory substances are known for myocarditis, dilated cardiomyopathy and heart failure, and all are believed to be causative substances, no fundamental therapy exists as a countering treatment.
The present invention provides drugs that are useful for the prevention and treatment of myocarditis, dilated cardiomyopathy and heart failure caused by excessive production of inflammatory mediators. The invention also provides drugs which are useful for prevention and treatment of these conditions and have effects of improving survival rates for the conditions, suppressing necrosis of cardiac muscle cells and diminishing or eliminating infiltration of inflammatory cells into the heart.
As a result of diligent research toward solving the aforementioned problems, the present inventors have discovered, surprisingly, that compounds with an inhibitory effect on NF-xcexaB suppress cardiac necrosis and infiltration of inflammatory cells into normal cardiac of heart tissue. More surprisingly, it was found that survival rates are also improved, and the present invention has thus been completed.
The present invention therefore provides preventive or therapeutic agents for myocarditis, dilated cardiomyopathy and heart failure comprising NF-xcexaB inhibitor as an active ingredient.